Gilead Sciences Inc v. Apotex Inc

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: Gilead Sciences, Inc. (Delaware)
  • Defendant: Apotex, Inc. (Canada), Lupin Limited (India), Laurus Labs Limited (India), and others.
  • Plaintiff’s Counsel: Fish & Richardson P.C.
• Case Identification: 1:20-cv-00189, D. Del., 10/18/2021
• Venue Allegations: Venue is alleged to be proper as Defendants are foreign corporations subject to personal jurisdiction in the District of Delaware or, for U.S.-based entities, are incorporated in Delaware.
• Core Dispute: Plaintiff alleges that Defendants' filing of Abbreviated New Drug Applications (ANDAs) seeking to market generic versions of Plaintiff's tenofovir alafenamide (TAF)-based antiviral drugs—VEMLIDY, DESCOVY, and ODEFSEY—constitutes infringement of four U.S. patents.
• Technical Context: The technology concerns antiviral drug development, specifically phosphonate nucleotide analogue prodrugs designed to improve the delivery and efficacy of treatments for HIV and Hepatitis B Virus (HBV).
• Key Procedural History: The case was initiated under the Hatch-Waxman Act following Defendants' submission of ANDAs and Paragraph IV certifications challenging the patents-in-suit. This filing is a Second Amended Complaint, adding allegations related to additional notice letters received by the Plaintiff from various Defendants.

Case Timeline

Date	Event
2000-07-21	Priority Date for ’791 and ’788 Patents
2008-06-24	U.S. Patent No. 7,390,791 Issues
2010-09-28	U.S. Patent No. 7,803,788 Issues
2011-08-16	Priority Date for ’065 and ’769 Patents
2014-06-17	U.S. Patent No. 8,754,065 Issues
2016-03-29	U.S. Patent No. 9,296,769 Issues
2019-12-30	Apotex sends VEMLIDY, DESCOVY, and ODEFSEY Notice Letters
2020-01-02	Lupin sends VEMLIDY, DESCOVY, and ODEFSEY Notice Letters
2020-01-06	Laurus Labs sends First VEMLIDY Notice Letter
2020-01-07	Natco sends First DESCOVY Notice Letter
2020-01-09	Cipla sends First ODEFSEY Notice Letter
2020-01-10	Cipla sends First and Second DESCOVY Notice Letters
2020-01-14	Macleods sends DESCOVY Notice Letter
2020-01-15	Hetero sends First VEMLIDY and DESCOVY Notice Letters
2021-10-18	Plaintiff files Second Amended Complaint

II. Technology and Patent(s)-in-Suit Analysis

U.S. Patent No. 7,390,791 - "Prodrugs of Phosphonate Nucleotide Analogues"

The Invention Explained

• Problem Addressed: The patent describes the challenge of delivering phosphonate nucleotide analogues, a class of antiviral drugs, to target tissues effectively. Traditional formulations were selected for systemic effect, which required rapid conversion to the parent drug in the bloodstream, but this did not ensure that the drug became enriched at the specific sites of viral replication, such as lymphoid tissues for HIV. (’791 Patent, col. 6:39-44).
• The Patented Solution: The invention discloses specific prodrugs—mixed ester-amidates of the nucleotide analogue PMPA (tenofovir)—that are designed to enhance delivery to and become concentrated within target tissues. (’791 Patent, col. 6:44-50). This selective enrichment is achieved through a specific chemical structure that is preferentially taken up or metabolized within target cells, such as those comprising lymphoid tissue, before converting to the active antiviral agent. (’791 Patent, Abstract; col. 6:63-65).
• Technical Importance: This prodrug strategy allows for higher concentrations of the active drug in target cells while maintaining lower concentrations in the blood plasma, which suggests a potential for increased efficacy with a more favorable safety profile. (’791 Patent, Fig. 3).

Key Claims at a Glance

• Asserted Independent Claim: The complaint asserts claim 7 against several defendants (Compl. ¶547, ¶630, ¶1077, ¶1159, ¶1453).
• Essential Elements of Claim 7:
  • A diastereomerically enriched compound having the specific chemical structure of 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine.
  • The claim also covers the compound's salts, tautomers, free base, and solvates.
• The complaint reserves the right to assert additional claims. (Compl. ¶547, n.17).

U.S. Patent No. 7,803,788 - "Prodrugs of Phosphonate Nucoleotide [sic] Analogues"

The Invention Explained

• Problem Addressed: As with the related ’791 Patent, this patent addresses the technical problem of effectively delivering phosphonate nucleotide antivirals to target tissues to maximize therapeutic effect while minimizing systemic exposure. (’788 Patent, col. 6:40-45).
• The Patented Solution: The patent claims a method of antiviral therapy that uses the specific tenofovir prodrug identified in the ’791 Patent. The solution is not the compound itself, but the act of administering it to treat viral infections. (’788 Patent, col. 8:46-51; Abstract). The patent explains that the prodrug's stereochemistry is influential in achieving the desired therapeutic enrichment in target tissues. (’788 Patent, col. 6:50-54).
• Technical Importance: Claiming the method of use provides a different layer of protection for the invention, covering the therapeutic application of the novel compound.

Key Claims at a Glance

• Asserted Independent Claim: The complaint asserts claim 7 against Cipla. (Compl. ¶1177, ¶1190, ¶1291).
• Essential Elements of Claim 7:
  • A method for antiviral therapy.
  • Comprising administering a therapeutically effective amount of a diastereomerically enriched compound having the specific chemical structure of 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine.
  • The claim also covers administering its salts, tautomers, free base, and solvates.
• The complaint reserves the right to assert additional claims. (Compl. ¶1177, n.61).

U.S. Patent No. 8,754,065 - "Tenofovir Alafenamide Hemifumarate"

Technology Synopsis

This patent is directed to a specific crystalline salt form—a hemifumarate—of the tenofovir alafenamide compound disclosed in the earlier patents. The patent explains that this specific salt form possesses advantageous properties over a previously disclosed monofumarate form, including improved stability and superior process reproducibility. (’065 Patent, col. 5:6-10).

Asserted Claims

Claim 1 is asserted against all defendants. (e.g., Compl. ¶283).

Accused Features

Defendants' ANDA products are alleged to be or contain the claimed tenofovir alafenamide hemifumarate salt. (Compl. ¶284).

U.S. Patent No. 9,296,769 - "Tenofovir Alafenamide Hemifumarate"

Technology Synopsis

This patent claims a composition containing the tenofovir alafenamide hemifumarate salt that is substantially free of a particular diastereomeric impurity and the monofumarate form. The invention provides a drug product with a specific purity profile, claiming compositions containing less than about 5% by weight of tenofovir alafenamide monofumarate. (’769 Patent, Abstract; col. 12:46-51).

Asserted Claims

Claim 1 is asserted against all defendants. (e.g., Compl. ¶316).

Accused Features

Defendants' ANDA products are alleged to be compositions comprising tenofovir alafenamide hemifumarate that meet the claimed purity limitation. (Compl. ¶317).

III. The Accused Instrumentality

Product Identification

The accused instrumentalities are the generic versions of Gilead’s TAF-containing products VEMLIDY, DESCOVY, and ODEFSEY, for which the Defendants have filed ANDAs with the U.S. Food and Drug Administration (FDA) (Compl. ¶1-2).

Functionality and Market Context

The products are oral tablets for the treatment of chronic hepatitis B (VEMLIDY) or HIV-1 infection (DESCOVY, ODEFSEY) (Compl. ¶102, ¶108, ¶114). The active pharmaceutical ingredient at issue is tenofovir alafenamide (TAF), which is administered as a hemifumarate salt (Compl. ¶104, ¶110, ¶116). The complaint alleges that by filing their ANDAs, Defendants have necessarily represented to the FDA that their proposed generic products contain the same active ingredient, have the same dosage form and strength, and are bioequivalent to Gilead’s approved products (Compl. ¶124, ¶133, ¶142).

IV. Analysis of Infringement Allegations

’791 Patent Infringement Allegations

Claim Element (from Independent Claim 7)	Alleged Infringing Functionality	Complaint Citation	Patent Citation
A diastereomerically enriched compound [having the specific chemical structure of 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine]	The complaint alleges that Lupin's VEMLIDY ANDA Product contains a "diastereomerically enriched compound" with the claimed chemical structure. The complaint includes a visual representation of this structure.	¶548	col. 7:12-20
and/or its salts, tautomers, free base and solvates.	The allegation encompasses not just the base compound but also its salts and other forms.	¶548	col. 7:18-20

’788 Patent Infringement Allegations

Claim Element (from Independent Claim 7)	Alleged Infringing Functionality	Complaint Citation	Patent Citation
A method for antiviral therapy	The complaint alleges that Cipla’s proposed product label will instruct for its use in antiviral therapy.	¶1178	col. 26:10-11
comprising administering a therapeutically effective amount of a diastereomerically enriched compound [having the specific chemical structure of 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine]	The complaint alleges Cipla's proposed label will direct the administration of a "therapeutically effective amount of a diastereomerically enriched compound" matching the claimed structure for treating HIV-1.	¶1178, ¶1193	col. 26:12-19
and its salts, tautomers, free base and solvates.	The alleged administration instructions in the proposed label encompass the compound's salts and other forms.	¶1191	col. 26:19-20

• Identified Points of Contention:
  • Scope Questions: A central question for the '791, '065, and '769 patents is one of chemical identity: will the Defendants' final, manufactured generic products contain the specific diastereomerically enriched compound, in the specific hemifumarate salt form, and with the specific level of purity required by the respective claims? The complaint provides a visual of the claimed chemical structure, alleging that Defendants' products contain this compound. (Compl. ¶548).
  • Technical Questions: For the '788 method of treatment patent, a key question will be whether the language in the Defendants' proposed product labels will be found to actively encourage or instruct physicians to administer the generic drug in a manner that directly infringes the claimed method, thus establishing induced infringement.

V. Key Claim Terms for Construction

• The Term: "diastereomerically enriched" (’791 Patent, claim 7; ’788 Patent, claim 7)

• Context and Importance: This term defines the required stereochemical purity of the active ingredient. The scope of "enriched" will be critical for determining infringement, as it establishes the threshold purity a generic product must possess to fall within the claim. Practitioners may focus on this term because the patents' own specification provides a quantitative definition that could significantly narrow its scope.

• Intrinsic Evidence for Interpretation:

  • Evidence for a Broader Interpretation: A party might argue that the plain and ordinary meaning of "enriched" simply means that one diastereomer is present in an amount greater than the other (i.e., >50%).
  • Evidence for a Narrower Interpretation: The specification states that "substantially homogeneous or chirally enriched" means the desired stereoisomer "constitutes greater than about 60% by weight of the compound, ordinarily greater than about 80% and preferably greater than about 95%." (’791 Patent, col. 8:37-41). This language provides strong intrinsic evidence for a construction requiring a specific, high level of purity.

• The Term: "less than about 5% by weight" (’769 Patent, claim 1)

• Context and Importance: This term sets the upper limit for a specific impurity (tenofovir alafenamide monofumarate) in the claimed composition. The construction of "about" will determine how much deviation from the 5% threshold is permissible, which could be dispositive for infringement if a generic product contains an impurity level close to this boundary.

• Intrinsic Evidence for Interpretation:

  • Evidence for a Broader Interpretation: A party could argue that "about" should be given its ordinary meaning of "approximately," allowing for some reasonable flexibility above the 5% mark, consistent with standards in the pharmaceutical field.
  • Evidence for a Narrower Interpretation: Gilead may argue that in the context of pharmaceutical purity, "about" accommodates only minor variations consistent with measurement precision and does not materially extend the 5% limit. The patent does not provide an explicit definition, leaving the term open to construction based on its use in the art.

VI. Other Allegations

• Indirect Infringement: The complaint alleges both induced and contributory infringement. Inducement is primarily based on allegations that Defendants' proposed product labels will instruct physicians and healthcare providers to administer the generic products for the patented uses, with knowledge and intent that such use will cause infringement (e.g., Compl. ¶299-303, ¶1195-1197). Contributory infringement is alleged on the basis that the accused products are especially made or adapted for an infringing use and are not suitable for substantial non-infringing use (e.g., Compl. ¶304, ¶1198).
• Willful Infringement: Willfulness is alleged based on Defendants' pre-suit knowledge of the patents-in-suit, stemming from at least their listing in the FDA's Orange Book and the Paragraph IV notice letters sent to Gilead (e.g., Compl. ¶295-296, ¶1189-1191). The complaint further designates the case as "exceptional" under 35 U.S.C. § 285, seeking enhanced damages and attorneys' fees (Compl. ¶1551-1552, Prayer for Relief ¶G).

VII. Analyst’s Conclusion: Key Questions for the Case

• A core issue will be one of chemical and compositional identity: Will discovery and testing of the Defendants' ANDA products confirm that they contain tenofovir alafenamide in the specific "diastereomerically enriched" form, as the claimed "hemifumarate" salt, and meeting the claimed purity level of "less than about 5%" of the monofumarate impurity? The case may turn on a series of detailed factual findings from chemical analysis.
• A second central question will be one of induced infringement: Does the language in the Defendants' proposed product labels, as submitted to the FDA, contain sufficient affirmative instruction and encouragement to meet the legal standard for inducing physicians and patients to perform the antiviral treatment methods claimed in the ’788 Patent?
• Finally, a key legal battle will likely be one of claim construction: The ultimate infringement determination may depend on how the court construes the scope of critical terms such as "diastereomerically enriched" and "about," which will set the precise boundaries of Gilead's patent rights.